The space where the club is located was originally a jazz bar called the Melody Room, a hang out of mobsters Bugsy Siegel and Mickey Cohen.[1] In the 1970s and 1980s it operated as a club called The Central, which was close to shutting down before Chuck E. Weiss, who had performed there for years, suggested to Depp that they revitalize the spot and rename it "The Viper Room".[2]Tom Waits also had a hand in redeveloping the spot.[3]

While predominantly known as a music venue, The Viper Room also hosts a lower level below the stage and audience area which is home to a large and well stocked whiskey bar. The whiskey bar boasts a diverse selection, ranging from Jack Daniel's, Crown Royal, and other commonly available whiskeys, to rarer or more local whiskeys such as Slow Hand White Whiskey, Hochstadter's Slow & Low Rock & Rye, and numerous types of small batch whiskey.

In the 1983 film Valley Girl, the building (then housing a nightclub called The Central) was used for scenes featuring the new-wave band the Plimsouls. In Oliver Stone’s film The Doors (1991), the building was used as a filming location for scenes depicting the London Fog, also of West Hollywood. London Fog was a lesser-known nightclub next to the Whisky a Go Go where the Doors had their first regular gigs for four months in early 1966.[7]

The Viper Room is also featured in the 2004 documentary DiG! when members of the band the Brian Jonestown Massacre began brawling with each other on stage while performing.

As part of the settlement of a lawsuit involving the disappearance of co-owner Anthony Fox in 2001, Depp relinquished his ownership of the Viper Room in 2004.[8] Until early 2008, the club was owned by Darin Feinstein, Bevan Cooney, and Blackhawk Capital Partners, Inc. The club is currently partly owned by Harry Morton,[9] President and CEO of Pink Taco, the son of Hard Rock Cafe co-founder Peter Morton and Darin Feinstein. Morton plans to turn the gritty Sunset Strip club into a global franchise by opening several live music venues throughout the world, all of which will bear the name "The Viper Room".[10][11]

A nightclub located in Cincinnati, Ohio, was formerly called "The Viper Room". The club changed its name to "The Poison Room" on January 1, 2006, after they were told by the West Hollywood Viper Room to stop using the name.[12] Another "Viper Room" in Portland, Oregon, has also been told to stop using the name under threat of a trademark lawsuit, with owner Darin Feinstein claiming "Every dollar they make is the result of using our name."[13] Additionally, there is a legal brothel in Brisbane, Australia called 'The Viper Room'. There is also a nightclub in Stockholm, Sweden, "as well as ones in Harrogate, UK, Vienna, Austria, and another in Sheffield UK similarly named." Until February 2009 there was a nightclub with the same name in Melbourne, Australia; it was closed down due to a spate of violent incidents that included two shootings as well as license breaches and the arrest of a co-owner on drug charges.[14] On April 16, 2011, a nightclub named "The Viper Room" opened its doors in the city of Nijmegen in the Netherlands. The club is named after the club in Hollywood and is decorated in the same style as the US club.[15]